WO2007122274A1 - Composés inhibiteurs d'acétylcholinestérase utilisés dans le traitement de la maladie d'alzheimer - Google Patents

Composés inhibiteurs d'acétylcholinestérase utilisés dans le traitement de la maladie d'alzheimer Download PDF

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WO2007122274A1
WO2007122274A1 PCT/ES2007/000237 ES2007000237W WO2007122274A1 WO 2007122274 A1 WO2007122274 A1 WO 2007122274A1 ES 2007000237 W ES2007000237 W ES 2007000237W WO 2007122274 A1 WO2007122274 A1 WO 2007122274A1
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methyl
compound according
compound
tetrahydroacridine
mmol
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PCT/ES2007/000237
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Spanish (es)
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Pelayo Camps García
Diego MUÑOZ-TORRERO LÓPEZ-IBARRA
Xavier FORMOSA MÁRQUEZ
Michele Scarpellini
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Universidad De Barcelona
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9

Definitions

  • Acetylcholinesterase inhibitor compounds for the treatment of Alzheimer's disease are Acetylcholinesterase inhibitor compounds for the treatment of Alzheimer's disease
  • the invention relates to acetylcholinesterase inhibitor compounds and a process for their preparation. It also refers to pharmaceutical compositions comprising said compounds and their use for the treatment of Alzheimer's disease.
  • Alzheimer's disease the most common form of dementia in the elderly, is one of the biggest health problems in developed countries along with cardiovascular disorders and cancer.
  • This slow, progressive and finally fatal neurodegenerative disorder is characterized clinically by a notable cognitive decline defined by a loss of memory and learning capacity, together with a reduced ability to develop basic activities of daily life, and a wide range of neuropsychiatric symptoms such such as apathy, verbal and physical agitation, irritability, anxiety, depression, delusions and hallucinations.
  • Alzheimer's disease currently affects approximately 20 million people worldwide, and this amount will increase substantially in the future as the number of elderly people in the population increases, taking into account that the prevalence of Alzheimer's disease doubles every 5 years from 65, with 47% affected among those over 85 years.
  • Alzheimer's disease As a result of the increasing incidence and the devastating effects of this disease, there is an urgent and growing need for effective pharmacotherapy.
  • the multifaceted nature of Alzheimer's disease has led to the development of a variety of approaches for its pharmacological correction. Although enormous progress has been made in the identification of the molecular origins of Alzheimer's disease, there is currently no cure for this disease.
  • Alzheimer's disease is characterized by two main pathological aspects: amyloid plaques and neurofibrillar clews, in addition to the loss of neuronal cells in specific regions of the brain.
  • Different strategies have been developed aimed at reducing, preventing or even reversing the generation and deposition of A ⁇ with the idea of reducing the rate of progress of the disease and preventing further losses of neuronal cells.
  • Alzheimer's disease in particular the treatment of cognitive deficits, has been successfully addressed through the replacement of deficient neurotransmitters, especially acetylcholine, in the CNS of patients in Ia Alzheimer disease.
  • AChE acetylcholinesterase
  • the most established therapeutic approach for Alzheimer's disease involves the use of a group of indirect colinomimetic agents with the pharmacological profile of AChE inhibitors (tacrine, donepezil, rivastigmine and galantamine), which increase the central cholinergic neurotransmission inhibiting the degradation of Acetylcholine
  • AChE inhibitors have been shown to be a class of effective medications to improve cognitive function and activities of daily living, and generally have favorable tolerability and safety profiles. Recent evidence suggests that the AChE enzyme also has non-cholinergic secondary functions. Thus, while AChE has a non-cholinergic neurotrophic activity, it can also play a key role in the development of senile plaques, by accelerating the deposition of A ⁇ .
  • the design and synthesis of new AChE inhibitors capable of interacting simultaneously with the active site and with the peripheral site of the AChE enzyme (dual-binding AChE inhibitors) as candidates for anti-Alzheimer's drugs with potential to modify the disease currently constitute A very intense research area.
  • Donepezil the second anti-Alzheimer drug approved by the FDA, is the only AChE inhibitor of the dual binding site currently marketed, although it was not specifically designed as such.
  • the character of the dual-binding site inhibitor of donepezil may explain its excellent pharmacological profile.
  • WO 2004/032929 describes a family of heterodimers, containing the unit of donepezil ndanone and a tacrine residue, which behave as AChE inhibitors of dual binding site and that can be used for the treatment of Alzheimer's disease.
  • the inventors have found new compounds that behave as inhibitors of acetylcholinesterase dual binding site showing a high potency of AChE inhibition. Thus, these compounds are very promising agents for the treatment of Alzheimer's disease.
  • a compound of formula (I) 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, including any stereoisomer or mixture of stereoisomers wherein R 1 , R 2 , R 3 and R 4 are radicals independently selected from the group consisting of H, F, Cl, Br, CF 3 , (Ci-C 4 ) -alkyl, (CrC 4 ) -alkoxy and nitro; R 5 , Re, R 7 and Re are radicals independently selected from the group consisting of H and (Ci-C 6 ) -alkoxy; n is an integer from 3 to 5; r is an integer from 2 to 5; s is an integer from 1 to 5 and X is a birradical selected from CO and CH 2 .
  • Preferred compounds of formula (I) are those in which Ri, R 2 , R 3 and R 4 are radicals independently selected from the group consisting of H, F, Cl and Br; R5, R 6 , R 7 and Rs are radicals independently selected from the group consisting of H and methoxy, and s is 1.
  • Most preferred compounds of formula (I) are those in which R 2 is selected from H and Cl; R 1 , R 3 , R 4 , R 5 and R 8 are H; R 6 and R 7 are methoxy; n is an integer from 3 to 4; and r is an integer of 2 to 3.
  • Preferred pharmaceutically acceptable salts of the compounds of formula (I) are hydrochloride or dihydrochloride.
  • Another aspect of the present invention relates to a process for the preparation of compounds of formula (I), according to Scheme I. which comprises reacting an intermediate of formula (II) with an intermediate of formula (III), wherein the radicals and variables are as defined above for the corresponding compounds, and Rg is a radical selected from the group consisting of CF 3 , (CrC 4 ) -alkyl, phenyl, and phenyl mono- or disubstituted by a radical selected from (Ci- C 4 ) -alkyl, halogen and nitro; n is an integer from 3 to 5; and r is an integer from 2 to 5.
  • a pharmaceutically acceptable salt is desired, it is obtained by treatment with the corresponding acid.
  • a preferred acid is HCI.
  • the intermediates of formula (III) can be prepared by reacting a derivative of the acridine of formula (V) with an alkanolamine of formula (Vl), followed by reacting the hydroxyl group of the compound obtained with a sulfonyl chloride to give the corresponding sulfonate , according to Scheme II. where the radicals and variables have the values defined before.
  • the intermediates of formula (V) are either known in the art or are easily prepared by analogy with those known in the art.
  • the compounds of formula (I) can also be obtained through the procedure indicated in Scheme (III). which comprises reacting an intermediate of formula (VII) with an intermediate of formula (V).
  • Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, including any stereoisomer or mixture of stereoisomers, together with appropriate amounts of pharmaceutical excipients or carriers.
  • Example 17 illustrates that the compounds of the present invention are potent AChE inhibitors (of bovine or human erythrocytes), showing inhibitory concentrations, expressed as IC5 0 (nM), which are in the range of 0.09-5 nM, evaluated by the method described by Ellman et al.
  • the IC50 inhibitory concentrations (nM) of these compounds are considerably lower than those of chlorotacrine or donepezil.
  • the inhibitory concentrations CI5 0 (nM) of the compounds of the present invention are also considerably inferior. Consequently, these compounds are useful for the treatment of Alzheimer's disease with advantages over those known in the art.
  • the compounds of the present invention also inhibit butyrylcholinesterase (BChE), which may represent an advantage over other anti-Alzheimer's agents known in the art.
  • BChE butyrylcholinesterase
  • Recent tests have shown that, in patients with advanced Alzheimer's disease, AChE activity is greatly reduced in specific regions of the brain, while BChE activity increases (cf. Giacobini, E., Neurochem. Res 2003, vol. 28, pp. 515-522).
  • a further aspect of the present invention refers to the use of the compounds of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, including any stereoisomer or mixture of stereoisomers, for the preparation of a medicine for the prophylactic and / or therapeutic treatment of Alzheimer's disease in mammals, including humans.
  • the invention is also related to a method for the treatment or prophylaxis of a mammal, including a human being, who suffers or is susceptible to suffering from Alzheimer's disease.
  • Said method comprises administering to said patient a therapeutically effective amount of a compound of formula (I) defined above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, including any stereoisomer or mixture of stereoisomers, together with excipients or Pharmaceutical carriers
  • the solid was recrystallized from a methanol / ethyl acetate mixture in the ratio 1: 4 (5 mL / mmol). The solid was isolated by filtration and dried at 80 0 C / 30 Torr for 48 h to give the hydrochloride of Ia 9- ( ⁇ -hydroxyalkylamino) tetrahydroacridine as a solid light brown.
  • Example 3 9-f (3-hydroxypropyaminol-1, 2,3,4-tetrahydroacrylene hydrochloride.
  • Example 5 9 - [(2-methanesulfonyloxyl) amino1-1, 2,3,4-tetrahydroacridine.
  • an analytical sample of the hydrochloride was prepared as follows: the above compound (2.59 g, 7.3 mmol) was dissolved in methanol (20 ml_), the solution was filtered through a 0.45 ⁇ m PTFE filter , was treated with excess methanolic HCI solution (1.7 M, 14 ml_) and the solution was concentrated to dryness in vacuo. The solid (2.65 g) was recrystallized from methanol (10 mL).
  • This compound was obtained by the general method described above from 6- chloro-9- (3-hydroxypropylamino) -1, 2,3,4-tetrahydroacridine.
  • the crude product was used in the next stage without further purification (see examples 12 and 16).
  • This compound was obtained by the general method described above from 9- (2-methanesulfonyloxyethylamino) -1,2,3,4-tetrahydroacrylene (365 mg, 1,14 mmol) and 4 - [(5, 6-dimethoxyindan-2-yl) methyl] pperidine (306 mg, 11.11 mmol).
  • the analytical sample of the dihydrochloride was obtained in the manner described in the general method: from the base (114 mg, 0.23 mmol) the corresponding dihydrochloride monohydrate was obtained as a pale yellow solid (48 mg, 35% yield), mp 254 -255 0 C (methanol).
  • This compound was obtained by the general method described above from 6- chloro-9- (2-methanesulfonloxyethylamino) -1, 2,3,4-tetrahydroacridine (386 mg, 1, 20 mmol) and 4 - [( 5,6-dimethoxyindan-2-yl) methyl] piperidine (300 mg, 1.09 mmol).
  • the analytical sample of the dihydrochloride was obtained as described in the general method: from the base (165 mg, 0.31 mmol), the corresponding hydrated dihydrochloride was obtained as a slightly yellow solid (80 mg, 40% yield), mp 159-160 0 C (methanol).
  • Example 11 9- ⁇ (3- (4-r (5.6-dimethoxinin-2-i ⁇ met ⁇ piper ⁇ d ⁇ n-1-yl
  • This compound was obtained by the general method described above from 9- (3-methanesuIphonyloxypropylamino) -1, 2,3,4-tetrahydroacridine (294 mg, 0.88 mmol) and 4 - [(5,6- dmethoxyindan-2-yl) methyl] piperidine (242 mg, 0.88 mmol).
  • the analytical sample of the dihydrochloride was obtained as described in the general method: from the base (81 mg, 0.16 mmol), the corresponding hydrated dihydrochloride was obtained as a pale yellow solid (95 mg, 93% yield), mp 184-185 0 C (methanol).
  • Example 12 e-chloro-g-ffó ⁇ -rf ⁇ .e-dimethoxyindan ⁇ -iDmeti ⁇ piperidin-i- I) propyl) amine1-1, 2,3,4-tetrahydroacridine dihydrochloride
  • the analytical sample of the dihydrochloride was obtained as described in the general method: from the base (81 mg, 0.15 mmol), the corresponding hydrated dihydrochloride was obtained as a pale yellow solid (52 mg, 52% yield), mp 173-174 0 C (methanol).
  • This compound was obtained by the general method described above from 9- (2-methanesulfonyloxyethylamino) -1, 2,3,4-tetrahydroacridine (276 mg, 0.86 mmol) and 4 - [(5,6-dimethoxy- 1-oxoindan-2-yl) methyl] piperidine (249 mg, 0.86 mmol).
  • the analytical sample of the dihydrochloride was obtained as described in the general procedure: from the base (54 mg, 0.10 mmol), the corresponding hydrated dihydrochloride was obtained as a pale yellow solid (62 mg, 98% yield), mp 190-191 0 C (methanol).
  • IR (KBr), v (c ⁇ f 1 ): 3700-2400 (max. At 3401, 2928, 2871, 2718; + NH and CH st), 1685, 1672 (C O st), 1636, 1588, 1523, 1500 , 1458, 1363, 1317, 1266, 1220, 1120, 1037, 949, 863, 760.
  • This compound was obtained by the general method described above, from 6-chloro-9- (2-methanesulfonyloxyethylamino) -1, 2,3,4-tetrahydroacridine (305 mg, 0.86 mmol) and 4 - [(5 , 6-dimethoxy-1-oxoindan-2-yl) methyl] piperine (248 mg, 0.86 mmol).
  • the analytical sample of the dihydrochloride was obtained as described in the general method: from the base (168 mg, 0.31 mmol), the corresponding hydrated dihydrochloride was obtained as a beige solid (65 mg, 33% yield), mp 222-223 0 C (methanol).
  • IR (KBr) v (crrf 1 ): 3700-2400 (max. At 3375, 3259, 3125, 3051, 2927, 2854, 2792; + NH and CH st), 1687 (C O st), 1633, 1588, 1501, 1456, 1363, 1316, 1266, 1220, 1179, 1121, 1091, 1036, 949, 917, 884, 759.
  • This compound was obtained by the general method described above, from 9- (3-methanesulfonyloxypropylamino) -1, 2,3,4-tetrahydroacridine (80 mg, 0.24 mmol) and 4 - [(5,6-dimethoxy -1-oxoindan-2-yl) methyl] piperine (82 mg, 0.28 mmol).
  • the analytical sample of the dihydrochloride was obtained according to the general method: from the base (50 mg, 0.095 mmol), the corresponding hydrated dihydrochloride was obtained as a pale yellow solid (37 mg, 60% yield), mp 198-199 0 C (methanol).
  • IR (KBr), v (cnT 1 ): 3700-2400 (max. At 3435, 2930, 2706; + NH and CH st), 1690 (C O st), 1636, 1590, 1522, 1500, 1458, 1364 , 1316, 1265, 1121, 1036, 759.
  • Example 16 6-Chloro-9-r (3- (4-r (5.6-dimethox ⁇ -1 -oxo ⁇ ndan-2-Dmetillpiper ⁇ din-1 - hel) propyl) amino1-1, 2,3, 4-tetrahydroacridine dihydrochloride
  • the inhibitory activity of AChE was assessed spectrophotometrically at 25 0 C by the method of Ellman (see Ellman et to the., Biochem. Pharmacol. 1961, vol. 7, p. 88), using as substrate AChE from bovine or human erythrocytes and iodide of acetylthiocholine (0.53 mM or 0.27 mM for bovine and human AChE, respectively).
  • the reaction took place in a final volume of 3 mL of 0.1 M phosphate buffer solution pH 8.0, containing 0.025 units of AChE and a 333 ⁇ M solution of 5,5'-dithiobis acid (2-nitrobenzoic acid (DTNB) was used ) to produce the yellow anion of 5-thio-2-nitrobenzoic acid
  • the inhibition curves were carried out in triplicate by incubating with at least 12 inhibitor concentrations for 15 min. A triplicate sample without inhibitor was always present to know 100% of AChE activity
  • the reaction was stopped by the addition of 100 ⁇ L of 1 mM serine, and the color production was determined at 414 nm.

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Abstract

L'invention concerne des composés représentés par la formule (I), ainsi que leurs sels ou leurs solvates acceptables d'un point de vue pharmaceutique, y compris n'importe quel stéréoisomère ou mélange de stéréoisomères, formule dans laquelle R1, R2, R3 et R4 sont des radicaux sélectionnés indépendamment du groupe composé de H, Cl, F, Br, CF3, alkyle (C1-C4), alcoxyle (C1-C4) et nitro; R5, R6, R7 et R8 sont des radicaux sélectionnés indépendamment du groupe composé de H et alkoxyle (C1-C6); n est un entier de 3 à 5; r est un entier de 2 à 5; s est un entier de 1 à 5; et X est un biradical sélectionné parmi CO et CH2. Lesdits composés sont des inhibiteurs d'acétylcholinestérase à double site de liaison et sont utilisés comme principes actifs contre la maladie d'Alzheimer.
PCT/ES2007/000237 2006-04-20 2007-04-19 Composés inhibiteurs d'acétylcholinestérase utilisés dans le traitement de la maladie d'alzheimer WO2007122274A1 (fr)

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ES200601045A ES2288406B1 (es) 2006-04-20 2006-04-20 Compuestos inhibidores de acetilcolinesterasa para el tratamiento de la enfermedad de alzheimer.

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011076969A1 (fr) * 2009-12-23 2011-06-30 Universidad De Barcelona Composés multifonctionnels modificateurs de la maladie d'alzheimer pour le traitement de cette maladie
WO2011101774A1 (fr) 2010-02-16 2011-08-25 Pfizer Inc. (r)-4-((4-((4-(tétrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)méthyl) pipéridin-1-yl)méthyl)tétrahydro-2h-pyran-4-ole, agoniste partiel des récepteurs 5-ht4
US8349293B2 (en) 2007-03-22 2013-01-08 Guerbet Use of metal nanoparticles in the diagnosis of Alzheimer's disease
WO2013167711A1 (fr) 2012-05-10 2013-11-14 Universitat De Barcelona Composés à cibles multiples dirigés contre la protéine bêta-amyloïde pour le traitement de la maladie d'alzheimer
WO2014206877A1 (fr) 2013-06-27 2014-12-31 Universitat De Barcelona Composés médicamenteux à cibles multiples pour le traitement de troubles neurodégénératifs
CN104892489A (zh) * 2015-06-08 2015-09-09 扬子江药业集团江苏海慈生物药业有限公司 一种盐酸多奈哌齐杂质的制备方法
US9221760B2 (en) 2011-05-09 2015-12-29 Van Andel Research Institute Autophagy inhibitors

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Publication number Priority date Publication date Assignee Title
WO2001017529A1 (fr) * 1999-09-09 2001-03-15 Unitech Pharmaceuticals, Inc. Derives de tacrine destines au traitement de la maladie d'alzheimer
WO2004032929A2 (fr) * 2002-10-09 2004-04-22 Neuropharma, S.A. Inhibiteurs d'acetylcholinesterase a site de liaison double destines au traitement de la maladie d'alzheimer

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2001017529A1 (fr) * 1999-09-09 2001-03-15 Unitech Pharmaceuticals, Inc. Derives de tacrine destines au traitement de la maladie d'alzheimer
WO2004032929A2 (fr) * 2002-10-09 2004-04-22 Neuropharma, S.A. Inhibiteurs d'acetylcholinesterase a site de liaison double destines au traitement de la maladie d'alzheimer

Non-Patent Citations (1)

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Title
ALONSO D. ET AL.: "Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE", BIOORGANIC MEDICINAL CHEMISTRY, vol. 13, 2005, pages 6588 - 6597, XP005149599 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8349293B2 (en) 2007-03-22 2013-01-08 Guerbet Use of metal nanoparticles in the diagnosis of Alzheimer's disease
WO2011076969A1 (fr) * 2009-12-23 2011-06-30 Universidad De Barcelona Composés multifonctionnels modificateurs de la maladie d'alzheimer pour le traitement de cette maladie
ES2362591A1 (es) * 2009-12-23 2011-07-08 Universidad De Barcelona Compuestos multifuncionales modificadores de la enfermedad de alzheimer para el tratamiento de esta enfermedad.
WO2011101774A1 (fr) 2010-02-16 2011-08-25 Pfizer Inc. (r)-4-((4-((4-(tétrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)méthyl) pipéridin-1-yl)méthyl)tétrahydro-2h-pyran-4-ole, agoniste partiel des récepteurs 5-ht4
US9221760B2 (en) 2011-05-09 2015-12-29 Van Andel Research Institute Autophagy inhibitors
WO2013167711A1 (fr) 2012-05-10 2013-11-14 Universitat De Barcelona Composés à cibles multiples dirigés contre la protéine bêta-amyloïde pour le traitement de la maladie d'alzheimer
US9238626B2 (en) 2012-05-10 2016-01-19 Universitat De Barcelona Beta-amyloid-directed multitarget compounds for the treatment of alzheimer's disease
WO2014206877A1 (fr) 2013-06-27 2014-12-31 Universitat De Barcelona Composés médicamenteux à cibles multiples pour le traitement de troubles neurodégénératifs
EP2818467A1 (fr) 2013-06-27 2014-12-31 Universitat de Barcelona Composés de médicament multicible pour le traitement de troubles neurodégénératifs
CN104892489A (zh) * 2015-06-08 2015-09-09 扬子江药业集团江苏海慈生物药业有限公司 一种盐酸多奈哌齐杂质的制备方法

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